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Treatment of Elderly Patients with Isolated Systolic Hypertension with Isosorbide Dinitrate in an Asymmetric Dosing Schedule

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Treatment of Elderly Patients with Isolated Systolic Hypertension with Isosorbide Dinitrate in an Asymmetric Dosing Schedule Journal of Human Hypertension (1998) 12, 557–561 1998 Stockton Press. All rights reserved 0950-9240/98 $12.00 http://www.stockton-press.co.uk/jhh ORIGINAL ARTICLE Treatment of elderly patients with isolated systolic hypertension with isosorbide dinitrate in an asymmetric dosing schedule MJF Starmans-Kool1,4, HAJ Kleinjans3, FAT Lustermans1, JA Kragten1, JGS Breed2 and LMAB Van Bortel4 1Departments of Internal Medicine and Cardiology, De Wever Hospital Heerlen, 2St Jans Gasthuis Weert, 3Byk Nederland BV, 4Department of Pharmacology, Cardiovascular Research Institute Maastricht University, The Netherlands Nitrates decrease pulse pressure more than mean (17.9%) than with placebo (5%; P Ͻ 0.05). SBP and MAP arterial pressure (MAP) and are advocated for the treat- decreased compared to baseline, but the changes were ment of isolated systolic hypertension (ISH). Nitrates not statistically significant between the two groups. show drug tolerance during chronic treatment so an DBP tended to increase with ISDN compared to placebo. asymmetric dosing regimen may prevent loss of effect Mean 24-h, mean daytime and mean night-time pulse of nitrates. This study investigates the anti-hypertensive pressure decreased after treatment with ISDN (10.7%, effect of isosorbide dinitrate (ISDN) given in a twice 12.1%, 7.9%, respectively). Pulse pressure tended to daily asymmetric dosing regimen in elderly patients decrease more during the day than during the night with with ISH. ISDN. No changes could be demonstrated with placebo. After a 6-week placebo run-in period, patients entered In conclusion, pulse pressure decreased with ISDN, the double-blind study. Ten patients received placebo resulting in a lower SBP without a decrease in DBP. The and 11 patients ISDN 20 mg b.i.d. for 8 weeks. This dose latter may preserve coronary perfusion in ISH. With the could be doubled once. Office systolic and diastolic asymmetric dosing regimen the decrease in pulse blood pressures (SBP/DBP) and ambulatory BP were pressure was not clear at night. Whether a decrease in measured. Pulse pressure was calculated as SBP–DBP. nocturnal BP, in addition to the spontaneous decrease, Office pulse pressure was more reduced during ISDN is advisable in ISH remains a matter of debate. Keywords: isolated systolic hypertension; large arteries; anti-hypertensive therapy; nitrates; arterial compliance Introduction these studies have clearly demonstrated that SBP is an important and independent cardiovascular risk Isolated systolic hypertension (ISH) is characterised factor.2,6,9 by a disproportionate increase in systolic blood In patients with ISH mean arterial pressure (MAP) pressure (SBP) without an elevation of diastolic and vascular resistance may be normal or slightly blood pressure (DBP). In general, ISH is defined by elevated, while pulse pressure, the difference a SBP above 160 mm Hg and a DBP below 90–95 10–12 1 between SBP and DBP, is increased. It has been mm Hg. shown that an increase in pulse pressure contributes Several studies have shown that SBP increases 2,3 considerably to the increase in cardiovascular mor- with age. As DBP decreases after 50 years of age, bidity and mortality seen at higher ages.13 Pulse pulse pressure increases. It has been demonstrated pressure, for a given stroke volume, is determined that the prevalence of ISH increases with age from 3–5 by the ejection rate of the left ventricle, the timing approximately 5% at 60 to 24% at 80 years. Since of reflected waves and the visco-elastic properties of the number of elderly people is still rising, ISH and the arterial wall, such as large artery compliance.12–14 its complications is becoming a major public health In elderly patients with ISH (Ͼ50 years of age) the issue. Epidemiological studies have shown an increase in pulse pressure is mainly due to a direct increased risk of stroke and cardiovascular mor- 2,4,6–8 decrease in large artery compliance and to an bidity and mortality with ISH. In addition, indirect lowering of arterial compliance by an increase in early pulse wave reflections. The SHEP study and SYST-EUR have shown that Correspondence: Dr MJF Starmans-Kool, Department Pharma- 4,8 cology, Maastricht University, PO Box 616, 6200 MD Maastricht, patients with ISH benefit from treatment. Classical The Netherlands anti-hypertensive drugs decrease SBP as well as Received 5 January 1998; revised 22 April 1998; accepted 1 DBP. DBP determines coronary perfusion and thus May 1998 influences an adequate oxygen supply to the heart.15 ISDN treatment of elderly ISH patients MJF Starmans-Kool et al 558 A curvilinear (J-shaped curve) relation has been the last 3 months, unstable angina, severe anaemia, described for the extent of BP reduction through renal or hepatic disease, neurologic abnormalities, anti-hypertensive therapy and the occurrence of pulmonary or endocrine disease except non-insulin myocardial infarction.16,17 The J-curve was seen dependent diabetes mellitus (NIDDM), peripheral especially in elderly patients.18 In ISH patients the arterial disease or treatment with other drugs known coronary system will be frequently narrowed to affect BP. because of atherosclerosis, while left ventricular At randomisation, patients should have a sitting hypertrophy will impair metabolic supply in case of DBP lower than 95 mm Hg and a SBP between 160 a large reduction in DBP.19 Consequently, with the and 200 mm Hg. Twenty-five patients were random- classical anti-hypertensive agents, a further decrease ised, 14 were subsequently treated with ISDN and of DBP in patients with coronary artery disease and 11 with placebo. Laboratory values showed no clini- ISH could be harmful.16,18,20 cally relevant abnormalities at randomisation in all Low-dose nitrates result in a selective dilation of patients. Demographic and haemodynamic para- large arteries, leading to an increase in arterial com- meters at randomisation are shown in Table 1. pliance, while almost no effect on arteriolar tone is present. In addition, nitrates are able to reduce wave Measurements reflection.3,10 As a consequence, nitrates can decrease SBP without a change in DBP.21 Therefore, Office measurements: All haemodynamic measure- nitrates have been advocated for the treatment of ments were performed in a sitting position after at ISH. However, the development of drug tolerance least 10 min of rest in a warm (22 ± 1°C) and quiet may limit the effect and use of nitrates as a therapy room. Measurements were repeated with at least a few for ISH. Using an eccentric dosing regimen, such as minutes interval. The mean of three measurements is used in patients with angina, this tolerance can was used as the average BP value. BP was measured be avoided.22 between 10 and 12 am with a mercury sphygmoman- The aim of the present study was to investigate ometer on the patient’s non-dominant arm. DBP was whether nitrates, given in an eccentric dosing sched- determined at Korotkoff’s phase V. Pulse pressure (PP) ule, can be effective and safe for the treatment of was calculated as SBP–DBP. MAP was calculated as elderly patients with ISH. SBP + 1/3DBP. Heart rate was determined by counting radial pulsations for 30 sec. Subjects and methods Ambulatory BP monitoring (ABPM): In a subset of Study design centres a 24-h ABPM was performed using a Space- labs 90207 monitor (Spacelabs Inc, Redmond, WA, The study was designed as a multicentre, double- USA). During the day (7 am to 11 pm) BP was blind, placebo-controlled, randomised, parallel recorded every 15 min, during the night (11 pm to study. After a 6-week placebo run-in period, 7 am) every 30 min. Patients were instructed to stop patients were randomised. BP and heart rate muscular activity and to keep their arms entirely measurements were performed at the recruitment quiet during the measurements. visit, 3 weeks before randomisation and at ran- domisation. Patients were included on the basis of Drug adherence: Patients were asked for their drug BP at randomisation. They were given placebo or adherence at the end of the 8-week treatment period isosorbide dinitrate (ISDN) for 8 weeks. The patients and the number of tablets was counted. started with ISDN 20 mg b.i.d. or placebo. If, after 2 weeks, SBP remained above 160 mm Hg, the dose could be doubled once. To avoid drug tolerance, Data analysis patients were asked to take the medication at 8 am Protocol-correct analysis was performed on all and 2 pm. Before, after 2 weeks, and at the end of patients who completed the study. In addition, an the 8-week treatment period, BP and heart rate intention-to-treat analysis was performed on all ran- measurements were performed. The study was approved by the ethics committees of the different centres and was performed in Table 1 Patient characteristics at randomisation accordance with the Declaration of Helsinki (revised Placebo ISDN version 1983). No. 11 14 Male/female 5/6 5/9 Patients Age (years) 71 (59–80) 69 (54–80) Length (cm) 167 (158–178) 164 (150–188) Thirty-one ISH patients of either sex between 60 and Weight (kg) 67 (53–83) 72 (51–87) 80 years of age were selected from the out-patient SBP (mm Hg) 177 ± 12 184 ± 9 clinics. Demographic data were collected and DBP (mm Hg) 84 ± 585± 5 patients were checked for exclusion criteria. In MAP (mm Hg) 115 ± 5 118 ± 3 ± ± addition, a general physical examination and a rou- PP (mm Hg) 92 4989 Heart rate (beats/minute) 72 ± 677± 12 tine laboratory screening were carried out. Informed consent was obtained from all patients. SBP: systolic blood pressure; DBP: diastolic blood pressure; MAP: Major exclusion criteria were a history of myocar- mean arterial pressure; PP: pulse pressure.
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